Opioids remain the most effective pharmacotherapeutics for the treatment of many chronic pain conditions. However, the potential for misuse of opioids can impact the decision to use them, particularly in the treatment of non-cancer pain. Opioid tolerance, dependence, addiction and some chronic pain conditions all share common mechanisms of neuronal adaptation. Consequently, distinguishing between these responses in an individual is challenging. Central drug delivery methods (e.g. intrathecal) enable some separation of chronic pain mechanisms (in large part spinally mediated) from those driving motivated behavior (supraspinally mediated). The proposed research program will use these techniques in experimental murine models of chronic pain to separate fentanyl self-administered (orally) for relief of chronic hyperalgesia from opioid self- administered in excess of that required for relief of hyperalgesia (anti-hyperalgesia). Experimental subjects with induced chronic neuropathic or cancer-evoked hyperalgesia of the hindpaw will be allowed to self-administer opioid orally under operant control daily for four weeks;the resulting anti-hyperalgesia will be determined after each operant session. Rescue anti-hyperalgesic agents will be administered intrathecally on various days after induction of hyperalgesia to assess the impact of spinal anti-hyperalgesia on opioid self-administration. Determining the effect of spinally administered rescue analgesic on opioid self-administration will enable an assessment of the amount of opioid administered for anti-hyperalgesia independent of that self-administered for supraspinally mediated reward. Those subjects continuing to self-administer opioid in the presence of adequate spinal analgesic will be further evaluated to determine supraspinal mechanisms that pre-dispose them to opioid self-administration in excess of that required for anti-hyperalgesia. Conversely, experimental subjects that reduce opioid self-administration in response to spinal analgesic (for alleviation of mechanical hyperalgesia) will be evaluated for factors that protect them from excess opioid self-administration. Clarification of the conditions under which opioids are misused when given for treatment of chronic pain may better inform the decision-to-treat process. PUBLIC HEALTH RELEVANCE: Chronic pain sufferers are thought to take opiate analgesics more for pain relief than in search of reward;however, fear of abuse liability often limits their use, resulting in undertreatment of chronic pain. The relationship between opiate self-administration and chronic pain intensity is rarely studied in experimental animals. Modeling opioid self- administration in mice experiencing chronic pain will provide insight into this concept and ultimately improve patient access to opioid therapy for their pain.